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FDA Panel Pans PTC’s Audacious Plan to Force Vote on Duchenne Drug

A panel of experts has voted against a Duchenne muscular dystrophy drug from PTC Therapeutics (NASDAQ: PTCT). The vote is a critical blow to the company’s unusual attempt to force the review of a drug the FDA has rejected twice already.

The 11 member committee, one of many that help the FDA evaluate drugs for approval, voted 10-1 that the data are inconclusive as to whether South Plainfield, NJ-based PTC’s drug, ataluren (Translarna), will help treat Duchenne, a muscle-wasting disease that robs boys of their ability to walk and kills them at an early age. The only committee member to vote in favor of ataluren was a patient representative.

“This could be great, but I don’t think we have the data yet to approve it,” Joel Perlmutter, a neurology professor at the Washington University School of Medicine, said of ataluren.

Aaron Kesselheim, an associate professor of medicine at Harvard Medical School, noted that most of PTC’s evidence came from analyses done after the data from ataluren’s trials had been revealed. “I’m concerned about the possibility of whether, consciously or subconsciously, there are ways that the reanalysis of data in that way can be misleading,” Kesselheim said.

That controversial drug, eteplirsen (Exondys 51), was developed by Sarepta Therapeutics (NASDAQ: SRPT), which had submitted data from a tiny, 12-patient trial. FDA scientists found the data inconclusive and a panel narrowly recommended against its approval.

But the support of top FDA drug evaluator Janet Woodcock and a highly mobilized patient community starving for an approved drug pushed eteplirsen to market nonetheless, causing a rift within the agency.

Duchenne is a genetic disease in which patients don’t produce the muscle-boosting protein dystrophin. Ataluren is designed to block the effects of so-called “nonsense mutations,” or genetic alterations that prevent patients from forming normal versions of dystrophin. Ataluren is meant to slow the progression of Duchenne for the 13 percent of patients with a nonsense mutation.

PTC argued that the “totality of the data” pooled from each of its studies show that ataluren can slow the progression of the disease. The company said that it identified a subgroup of patients within its latest trial, a 228-patient, placebo-controlled study, that benefited from ataluren. It went back to an earlier, smaller placebo-controlled study, and found patients with similar characteristics who also responded better to treatment. PTC contended these observations—along with trends favoring its drug on other measures, such as lung and muscle function—were enough to show that ataluren is an effective drug.

“We see remarkably consistency across both studies,” said Joseph McIntosh, PTC’s senior vice president and head of clinical development, at the hearing.

PTC took a few pages from Sarepta’s playbook, as well. It cited the pressing need for more Duchenne drugs. Eteplirsen is only approved for a small fraction of patients, and the only other FDA approved therapy, the steroid deflazacort (Emflaza), isn’t a cure. (PTC acquired it in March.) It has also leaned on the patient community for support. Many Duchenne patients and their caregivers showed up to the hearing, spoke of their positive experiences with ataluren, and pleaded with the panel to vote for the drug (A number of families disclosed that PTC paid for their travel expenses). And in its argument to the FDA this time, PTC has warned about the consequences of a “type 2 error” at the FDA—the failure to approve a drug only to find out later that it worked. Woodcock openly worried about making such a mistake when she spoke at Sarepta’s public hearing last year.

FDA scientists can be scathing in the briefing documents they release prior to an advisory committee hearing. The documents were particularly critical of PTC this time. The agency disagreed with PTC’s conclusions, provided an in-depth look at its exchanges with PTC over the years, and it chastised PTC for repeatedly trying to “explain away negative results on pre-specified analyses with novel theories developed with data in-hand.”

“Such conclusions are often very tempting, but are well-known to be highly prone to both known and unknown biases when generated with the full knowledge of a trial’s results,” FDA scientists wrote. The agency is “highly sensitive to the need to exercise regulatory flexibility in the setting of serious diseases like [Duchenne]. However, the critical requirement remains that substantial evidence of effectiveness be provided in order to support approval of a new drug.”

At today’s meeting, William Dunn, the director of the agency’s division of neurology products, noted that learning from a failed study and generating a new hypothesis is the “essence of scientific discovery.”

But Dunn was adamant that false conclusions can be reached by leaning on these analyses, whereas legitimate ones can only be reached if the new hypothesis is tested in a well-designed trial. The subgroup PTC now believes to respond the best to ataluren, for instance, is different than the group of patients it thought would best respond when it started its most recent trial. The FDA has argued this hypothesis should be tested in a new study. What PTC was presenting Thursday, Dunn said, were just “observations” that require more evaluation.

“We don’t object to looking at subgroups. But we don’t believe that you can save a failed study that way,” added Robert Temple, the director of the Office of Medical Policy for the FDA’s Center for Drug Evaluation.

Sarepta, meanwhile, won’t know conclusively for a few more years whether its own drug eteplirsen works. The FDA could theoretically pull eteplirsen from the market if a placebo-controlled trial, which has yet to begin, turns out negative. But the agency has only once withdrawn a so-called conditional approval.

Ben Fidler is Xconomy's Deputy Editor, Biotechnology. You can e-mail him at bfidler@xconomy.com Follow @benthefidler